TAK-243 (MLN7243)

A UAE inhibitor

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5mg

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货号: ajce49716
CAS: 1450833-55-2
别名: MLN7243
分子式: C19H20F3N5O5S2
分子量: 519.52
纯度: >98%
溶解度: DMSO : 50 mg/mL (96.24 mM);Water : 1 mg/mL (1.92 mM)
储存: Store at -20°C
库存: 现货

Background

MLN7243 is an inhibitor of ubiquitin-activating enzyme (UAE; IC₅₀ = 1 nM).¹ It is selective for UAE over NEDD8-activating enzyme (NAE), SUMO-activating enzyme (SAE), and the autophagy-activating enzyme ATG7 (IC₅₀s = 28, 850, and >10,000 nM, respectively). MLN7243 inhibits proliferation in a panel of 30 cancer cell lines (EC₅₀s = 0.006-1.1 ?M). It activates the unfolded protein response (UPR) and expansion of the endoplasmic reticulum surface area, a marker of ER stress, in HCT116 cells. In vivo, MLN7243 (12.5-25 mg/kg) reduces tumor growth in WSU-DLCL2, HCT116, Calu-6, THP-1, CWR22, HCC70, and MM.1S mouse xenograft models, as well as patient-derived xenograft (PDX) mouse models of colon, lung, breast, ovarian, and neck cancer.

1.Hyer, M.L., Milhollen, M.A., Ciavarri, J., et al.A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatmentNat. Med.24(2)186-193(2018)

Protocol

Cell experiment:

Normal keratinocytes (normal human keratinocytes (NHK) and recessive dystrophic epidermolysis bullosa keratinocytes (RDEBK)) and cSCC cell lines are seeded into 96 well plates and live cell number and cell death are analysed with an IncuCyte ZOOM real-time imager using the CellTox Green Cytotoxicity Assay. Relative EC50 values are determined using GraphPad Prism. For clonogenic assays cells are seeded into six well plates. Inhibitors (e.g., TAK-243; 0.01, 0.1, 1, and 10 μM) are added for the indicated times and then cells are maintained in drug-free medium for up to 2 weeks to allow colony formation. Colonies are fixed in 10% methanol, 10% acetic acid and stained with crystal violet[1].

Animal experiment:

Mice[2]The preclinical efficacy and toxicity of TAK-243 are assessed in mouse models of AML. OCI-AML2 cells are injected subcutaneously (sc) into SCID mice, and when tumors are palpable, mice are treated with TAK-243 (20 mg/kg sc twice weekly). As an additional model, primary AML cells from 2 patients are injected into the femurs of NOD-SCID mice. Two weeks after injection, mice are treated with TAK-243 (20 mg/kg sc twice weekly). After 3 weeks of treatment, mice ae sacrificed, and AML engraftment in the non-injected femur is measured by flow cytometry[2].

参考文献:

[1]. Hyer ML, et al. A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatment. Nat Med. 2018 Feb;24(2):186-193.
[2]. Best SR, et al. TAK-243, a small molecule inhibitor of ubiquitin-activating enzyme (UAE), induces ER stress and apoptosis in diffuse large B-cell lymphoma (DLBCL) cells. Blood 2017 130:1533.
[3]. Samir H. Barghout, et al. TAK-243 Is a Selective UBA1 Inhibitor That Displays Preclinical Activity in Acute Myeloid Leukemia (AML). Blood 2017, 130:814.